Fluoroergoline analogs

ABSTRACT

Provided herein are novel fluoroergoline derivatives and compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1D  and/or the 5-HT 1B  receptor, without agonizing the 5-HT 2B  receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the adrenergic alpha 2A  and/or the alpha 2B  receptors using the compounds and compositions disclosed herein.

This application is a continuation of U.S. patent application Ser. No.13/531,371, filed on Jun. 22, 2012, which claims priority under 35U.S.C. §119(e) from U.S. Provisional Application Ser. No. 61/571,299,filed on Jun. 23, 2011, which are hereby incorporated by reference intheir entirety.

FIELD

Provided herein are novel fluoroergoline derivatives and compositionsthereof. In other embodiments, provided herein are methods of treatment,prevention, or amelioration of a variety of medical disorders such as,for example, migraine using the compounds and compositions disclosedherein. In still other embodiments, provided herein are methods ofagonizing receptors such as, for example, the 5-HT_(1D) and/or the5-HT_(1B) receptor, without agonizing the 5-HT_(2B) receptor using thecompounds and compositions disclosed herein. In still other embodiments,provided herein are methods of antagonizing or inhibiting activity atreceptors such as, for example, the adrenergic alpha_(2A) and/or thealpha_(2B) receptors using the compounds and compositions disclosedherein.

BACKGROUND

Ergotamines such as, for example, dihydroergotamine mesylate are wellestablished therapeutic agents for the treatment of migraine. Morerecently, a number of highly selective agents for the treatment ofmigraine which have high 5-HT_(1D):5-HT_(1B) binding ratios have beenprepared, such as, for example, the alkyltryptamine derivatives(125-fold selectivity, Slassi, Bioorg. Med. Chem. Lett. 10: 1707-1709,(2000)), the indole series (300-fold selectivity, Castro, J. Med. Chem.41: 2667 (1998)) and from the non-indole series (>6000 fold selectivity,Ennis, J. Med. Chem. 41: 2180 (1998)). However, strong agonism of5-HT_(1B) by migraine therapeutics such as, for example, sumatriptan(Phebus, Cephalalgia 17: 245 (1997)) frequently leads to adversecardiovascular effects due to excessive vasoconstriction. Accordingly,an effective migraine agent should be selective for the 5-HT_(1D)receptor over the 5-HT_(1B) receptor, but with moderate agonism of the5-HT_(1B) receptor to minimize non-cranial vasoconstriction. Antagonismof adrenergic receptors, such as, for example, alpha_(1A), alpha_(1D),alpha_(2A), alpha_(2B) and alpha_(2C) by migraine therapeutics canreduce vasoconstriction caused by strong 5-HT_(1B) agonism.

Agonism of dopamine receptors is highly unfavorable for anti-migrainecompounds since nausea is a classic dopaminergic (activation of dopaminereceptors) symptom, which is already an indication of migraine itself.Yet another problem with many migraine therapeutics and especiallyergoline derivatives is undesirable agonism of 5-HT_(2B) receptors whichis associated with cardiac and non-cardiac fibrosis, includingcardiovascular valvulopathy (Rothman, Circulation 102: 2836 (2000)).Conversely, antagonism of 5-HT_(2B) receptors may offer therapeuticadvantages in the treatment and/or prevention of migraine (Schaerlinger,Br. J. Pharmacol. 140(2): 277-84, (2003)).

Accordingly, there is a continuing need for less toxic ergolinederivatives to treat and/or prevent disorders such as, for example,migraine, which selectively agonize 5-HT_(1D) receptors over 5-HT_(1B)receptors with moderated 5-HT_(1B) receptor agonism, have low dopaminereceptor agonism and are 5-HT_(2B) and adrenergic receptor antagonists.

SUMMARY

Provided herein are fluoroergoline derivatives which address these andother needs. In one aspect, the fluoroergoline derivatives describedherein include compounds of Formula (I) or (II):

or ion pairs, polymorphs, salts, hydrates or solvates thereof, wherein:

R₁ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)alkyl substituted with one or more fluorine atoms;

R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇;

R₃ is hydrogen, (C₁-C₃) alkyl, (C₁-C₃) substituted alkyl or (C₁-C₃)alkyl substituted with one or more fluorine atoms;

R₄ is

R₅ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl;

R₆ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl orsubstituted benzyl;

R₇ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substitutedbenzyl;

R₈ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀;

R₉ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃;

R₁₀ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆;

R₁₁ is (C₁-C₃) alkyl substituted with one or more fluorine atoms;

R₁₀₀-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

k is 0, 1 or 2; and

n is 0, 1, 2 or 3.

Also provided are derivatives, including salts, esters, enol ethers,enol esters, solvates, hydrates and prodrugs of the compounds describedherein. Further provided are compositions which include the compoundsprovided herein and a vehicle.

Methods of treating, preventing, or ameliorating symptoms of medicaldisorders such as, for example, migraine, ALS, Parkinson's disease,extra-pyramidal disorders, depression, nausea, restless legs syndrome,insomnia, aggression, Huntington's disease, dystonia, parsomnia andhyperlactinemia are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or compositionsthereof are administered to a subject.

Methods of antagonizing receptors such as, for example 5-HT_(2B),adrenergic receptors such as, for example, alpha_(1A), alpha_(1D),alpha_(2A), alpha_(2B) and alpha_(2C) with the compounds andcompositions described herein are also provided herein. In practicingthe methods, therapeutically effective amounts of the compounds orcompositions are administered.

Methods of agonizing receptors such as, for example, 5-HT_(1D) and5-HT_(1B), receptors with the compounds and compositions describedherein are also provided herein. In some embodiments, methods ofselectively agonizing the 5-HT_(1D) receptor over the 5-HT_(1B) receptorare provided. In other embodiments, methods of reducing agonism ofdopamine receptors when compared to agonism of dopamine receptors byother ergolines, such as, for example, dihydroergotamine, an existinganti-migraine agent, with the compounds and compositions describedherein are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or compositions areadministered.

DESCRIPTION OF THE FIGURES

FIG. 1 illustrates that 2-CF₃-dihydroergotamine has little agonistactivity against the 5-HT_(2B) receptor.

FIG. 2 illustrates potent antagonism of the 5-HT_(2B) receptor by2-CF₃-dihydroergotamine.

FIG. 3 illustrates that 2-CF3-dihydroergotamine behaves as an agonistwith both 5-HT_(1B) and 5-HT_(1D) and affords greater selectivity for5-HT_(1D) over 5-HT_(1B) (5-HT_(1D):5-HT_(1B) (30:1)).

FIG. 4 illustrates that both compounds (DHE and 2-CF3-DHE) weremetabolized by the human liver microsomes in the presence of NADPH withthe intrinsic clearance of 2-CF3-DHE being about 85% slower than that ofDHE.

FIG. 5 illustrates that 2-CF3-DHE (CBT001/02) displayed a slight meanincrease in tension as compared to positive control, sumatriptan (bothat concentrations from 100 pM to 10 μM) when tested in constrictionassays using human coronary arteries (n=6 for each condition).

FIG. 6 illustrates that 2-CF3-DHE (CBT001/02) displayed no change intension as compared to positive control, sumatriptan (both atconcentrations from 100 pM to 10 10 μM) when tested in constrictionassays using human saphenous veins (n=6 for each condition).

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there is aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

“Alkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, beta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl).

“Alkenyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl(isobutyl),2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-ylprop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls suchas but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R⁴⁰⁰, where R⁴⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₅-C₁₀) aryl.

“Compounds” refers to compounds encompassed by structural formulaedisclosed herein and includes any specific compounds within theseformulae whose structure is disclosed herein. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds described herein may contain one or more chiral centers and/ordouble bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds described herein include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, etc. In general,it should be understood that all isotopes of any of the elementscomprising the compounds described herein may be found in thesecompounds. Compounds may exist in unsolvated or unhydrated forms as wellas solvated forms, including hydrated forms and as N-oxides. In general,compounds may be hydrated, solvated or N-oxides. Certain compounds mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated herein and areintended to be within the scope of the present invention. Further, itshould be understood, when partial structures of the compounds areillustrated, that brackets indicate the point of attachment of thepartial structure to the rest of the molecule.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” bythemselves or as part of other substituents, refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and optionally any associated hydrogen atoms), are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomicgroups which can replace the carbon atoms include, but are not limitedto, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—, —S(O)₂NH— andthe like and combinations thereof. The heteroatoms or heteroatomicgroups may be placed at any interior position of the alkyl, alkenyl oralkynyl groups. Typical heteroatomic groups which can be included inthese groups include, but are not limited to, —O—, —S—, —O—O—, —S—S—,—O—S—, —NR⁵⁰¹R⁵⁰²—, ═N—N═, —N═N—, —N═N—NR⁵⁰³R⁴⁰⁴, —PR⁵⁰⁵—, —P(O)₂—,—POR⁵⁰⁶—, —O—P(O)₂—, —SO—, —SO₂—, —SnR⁵⁰⁷R⁵⁰⁸— and the like, where R⁵⁰¹,R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷ and R⁵⁰⁸ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism. Seee.g., (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism inPharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., NewYork, N.Y., 1999). The above methods for preparing hydrates are wellwithin the ambit of those of skill in the art, are completelyconventional and do not require any experimentation beyond what istypical in the art. Hydrates may be characterized and/or analyzed bymethods well known to those of skill in the art such as, for example,single crystal X-Ray diffraction, X-Ray powder diffraction, polarizingoptical microscopy, thermal microscopy, thermogravimetry, differentialthermal analysis, differential scanning calorimetry, IR spectroscopy,Raman spectroscopy and NMR spectroscopy. (Brittain, H., Chapter 6, pp.205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.),Marcel Dekker, Inc. New York, 1999). In addition, many commercialcompanies routine offer services that include preparation and/orcharacterization of hydrates such as, for example, HOLODIAG, PharmaparcII, Voie de l'Innovation, 27 100 Val de Reuil, France(http://www.holodiag.com).

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexylene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and optionally any associatedhydrogen atoms) are each independently replaced with the same ordifferent heteroatom. Typical heteroatoms to replace the carbon atomsinclude, but are not limited to, N, P, O, B, S, Si, etc. Specificallyincluded within the definition of “parent heteroaromatic ring system”are fused ring systems in which one or more of the rings are aromaticand one or more of the rings are saturated or unsaturated, such as, forexample, benzodioxan, benzofuran, chromane, chromene, indole, indoline,xanthene, etc. Typical parent heteroaromatic ring systems include, butare not limited to, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene and the like.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecompound in a preventative fashion. The application of a therapeutic forpreventing or prevention of a disease of disorder is known as‘prophylaxis.’ In some embodiments, the compounds provided hereinprovide superior prophylaxis because of lower long term side effectsover long time periods.

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. In some embodiments, the salt is pharmaceutically acceptable.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, but are not limited to, storage in an atmosphere containing asolvent, dosage forms that include the solvent, or routinepharmaceutical processing steps such as, for example, crystallization(i.e., from solvent or mixed solvents) vapor diffusion, etc. Solvatesmay also be formed, under certain circumstances, from other crystallinesolvates or hydrates upon exposure to the solvent or upon suspensionmaterial in solvent. Solvates may crystallize in more than one formresulting in solvate polymorphism. See e.g., (Guillory, K., Chapter 5,pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H.ed.), Marcel Dekker, Inc. New York, N.Y., 1999)). The above methods forpreparing solvates are well within the ambit of those of skill in theart, are completely conventional do not require any experimentationbeyond what is typical in the art. Solvates may be characterized and/oranalyzed by methods well known to those of skill in the art such as, forexample, single crystal X-Ray diffraction, X-Ray powder diffraction,polarizing optical microscopy, thermal microscopy, thermogravimetry,differential thermal analysis, differential scanning calorimetry, IRspectroscopy, Raman spectroscopy and NMR spectroscopy. (Brittain, H.,Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids,(Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition,many commercial companies routine offer services that includepreparation and/or characterization of solvates such as, for example,HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil,France (http://www.holodiag.com).

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), —NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) andNR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s are taken together with the nitrogen atomto which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, trihalomethyl, —CF₃, —CN,—OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O—P(O)(O⁻)₂, —P(O)(OR^(b))(O),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(S)OR^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a), R^(b) and R^(c) are aspreviously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S⁻, trihalomethyl, —CF₃, —CN, —NO, —NO₂,—S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(b),—NR^(b)C(NR^(b))R^(b) and NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a), R^(b)and R^(c) are as previously defined.

Substituent groups from the above lists useful for substituting otherspecified groups or atoms will be apparent to those of skill in the art.The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above. In some embodiments,substituents are limited to the groups above.

“Subject,” “individual” or “patient” is used interchangeably herein andrefers to a vertebrate, preferably a mammal. Mammals include, but arenot limited to, murines, rodents, simians, humans, farm animals, sportanimals and pets.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof,). Treatment may also be considered to includepreemptive or prophylactic administration to ameliorate, arrest orprevent the development of the disease or at least one of the clinicalsymptoms. Treatment can also refer to the lessening of the severityand/or the duration of one or more symptoms of a disease or disorder. Ina further feature, the treatment rendered has lower potential for longterm side effects over multiple years. In other embodiments “treating”or “treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the patient. In yet other embodiments,“treating” or “treatment” refers to inhibiting the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter) or both.In yet other embodiments, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, adsorption, distribution, metabolism andexcretion etc., of the patient to be treated.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a subject. In some embodiments, the vehicleis pharmaceutically acceptable.

Compounds

Provided herein are compounds of Formula (I) or (II):

or ion pairs, polymorphs, salts, hydrates or solvates thereof, whereinR₁ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄)alkyl substituted with one or more fluorine atoms; R₂ is alkyl,substituted alkyl, acyl, substituted acyl, halo, heteroalkyl,substituted heteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁,—NR₁₀₂R₁₀₃; —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇; R₃ is hydrogen, (C₁-C₃)alkyl, (C₁-C₃) substituted alkyl or (C₁-C₃) alkyl substituted with oneor more fluorine atoms; R₄ is

R₅ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl; R₆ is hydrogen,(C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substituted benzyl;R₇ is (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substitutedbenzyl; R₈ is hydrogen, OH, ═O, (C₁-C₄)alkyl, (C₁-C₄) substituted alkyl,—CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀; R₉ is hydrogen, OH, ═O, (C₁-C₄)alkyl, (C₁-C₄)substituted alkyl, —CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃; R₁₀ is hydrogen, OH, ═O,(C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₁₄ or —CONR₁₁₅R₁₁₆; R₁₁is (C₁-C₃) alkyl substituted with one or more fluorine atoms; R₁₀₀-R₁₁₆are independently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; k is 0, 1 or2; and n is 0, 1, 2 or 3.

In some embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms. In other embodiments, R₁ ishydrogen or (C₁-C₄) alkyl substituted with one or more fluorine atoms.In still other embodiments, R₁ is hydrogen, methyl or methyl substitutedwith one or more fluorine atoms. In still other embodiments, R₁ ishydrogen or methyl substituted with one or more fluorine atoms. In stillother embodiments, R₁ is hydrogen.

In some embodiments, R₂ is alkyl, acyl, halo, —NO₂, —OH, —S(O)_(k)R₁₀₀,—OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇. In otherembodiments, R₂ is alkyl, acyl, halo, —NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁,—NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —O₂CR₁₀₇ and n is 1. In stillother embodiments, R₂ is alkyl, halo and —OR₁₀₁ and n is 1. In stillother embodiments, n is 0.

In some embodiments, R₃ is hydrogen or (C₁-C₃) alkyl. In otherembodiments, R₃ is hydrogen or methyl. In still other embodiments, R₃ ishydrogen or methyl. In still other embodiments, R₃ is methyl. In stillother embodiments, R₃ is hydrogen.

In some embodiments, R₄ is

In other embodiments, R₄ is

In some embodiments, R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is (C₁-C₄)alkyl or substituted (C₁-C₄) alkyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl;R₉ is hydrogen, OH or (C₁-C₄) alkyl and R₁₀ is hydrogen, OH or (C₁-C₄)alkyl. In other embodiments, R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is(C₁-C₄) alkyl or substituted (C₁-C₄) alkyl 1; R₈ is hydrogen; R₉ ishydrogen, and R₁₀ is hydrogen. In still other embodiments, R₅ is (C₁-C₄)alkyl; R₆ is hydrogen; R₇ is benzyl or substituted benzyl; R₈ ishydrogen, OH or (C₁-C₄) alkyl; R₉ is hydrogen, OH or (C₁-C₄) alkyl andR₁₀ is hydrogen, OH or (C₁-C₄) alkyl. In still other embodiments, R₅ is(C₁-C₄) alkyl; R₆ is hydrogen; R₇ is benzyl or substituted benzyl; R₈ ishydrogen; R₉ is hydrogen, and R₁₀ is hydrogen.

In some embodiments, R₁₁ is methyl substituted with one or more fluorineatoms. In other embodiments, R₁₁ is —CF₃.

In some embodiments, R₁₀₀-R₁₂₂ are independently hydrogen, alkyl, orsubstituted alkyl, acyl or substituted acyl. In some embodiments,R₁₀₀-R₁₂₂ are independently hydrogen or alkyl.

In some embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, halo and—OR₁₀₁ and n is 0 or 1; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, (C₁-C₄) alkyl or benzyl; R₇ is(C₁-C₄) alkyl or benzyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉ ishydrogen, OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; andR₁₁ is methyl substituted with one or more fluorine atoms. In otherembodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkyl substitutedwith one or more fluorine atoms; R₂ is alkyl, halo and —OR₁₀₁ and n is 0or 1; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is (C₁-C₄) alkyl or is (C₁-C₄)substituted alkyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉ is hydrogen,OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; and R₁₁ ismethyl substituted with one or more fluorine atoms. In still otherembodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkyl substitutedwith one or more fluorine atoms; R₂ is alkyl, halo and —OR₁₀₁ and n is 0or 1; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is (C₁-C₄) alkyl or is (C₁-C₄)substituted alkyl; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; andR₁₁ is methyl substituted with one or more fluorine atoms. In stillother embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, halo and—OR₁₀₁ and n is 0 or 1; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is benzyl or substituted benzyl;R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉ is hydrogen, OH or (C₁-C₄)alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; and R₁₁ is methylsubstituted with one or more fluorine atoms. In still other embodiments,R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkyl substituted with one ormore fluorine atoms; R₂ is alkyl, halo and —OR₁₀₁ and n is 0 or 1; R₃ ishydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is benzyl or substituted benzyl;R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; and R₁₁ is methylsubstituted with one or more fluorine atoms.

In some embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, acyl, halo,—NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₅₀, —CO₂R₁₀₆ or—O₂CR₁₀₇; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, (C₁-C₄) alkyl or benzyl; R₇ is(C₁-C₄) alkyl or benzyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉ ishydrogen, OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; andR₁₁ is methyl substituted with one or more fluorine atoms.

In other embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₃ is hydrogen or (C₁-C₃)alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, (C₁-C₄) alkyl or benzyl; R₇ is(C₁-C₄) alkyl or benzyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉ ishydrogen, OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; R₁₁is methyl substituted with one or more fluorine atoms; and n is 0. Instill other embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₃ is hydrogen or (C₁-C₃)alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is (C₁-C₄) alkyl, substituted(C₁-C₄) alkyl, benzyl or substituted benzyl; R₈ is hydrogen, OH or(C₁-C₄) alkyl; R₉ is hydrogen, OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OHor (C₁-C₄) alkyl; R₁₁ is methyl substituted with one or more fluorineatoms; and n is 0. In still other embodiments, R₁ is hydrogen, (C₁-C₄)alkyl or (C₁-C₄) alkyl substituted with one or more fluorine atoms; R₃is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen; R₇ is (C₁-C₄) alkyl, substituted(C₁-C₄) alkyl, benzyl or substituted benzyl; R₈ is hydrogen; R₉ ishydrogen; R₁₀ is hydrogen; R₁₁ is methyl substituted with one or morefluorine atoms; and n is 0.

In still other embodiments, R₁ is hydrogen; R₂ is alkyl, acyl, halo,—NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₅₀, —CO₂R₁₀₆ or—O₂CR₁₀₇; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₇ is (C₁-C₄) alkyl or benzyl; R₈ is hydrogen, OH or (C₁-C₄) alkyl; R₉is hydrogen, OH or (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl;and R₁₁ is methyl substituted with one or more fluorine atoms.

In still other embodiments, R₁ is hydrogen, (C₁-C₄) alkyl or (C₁-C₄)alkyl substituted with one or more fluorine atoms; R₂ is alkyl, acyl,halo, —NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅,—CO₂R₁₀₆ or —O₂CR₁₀₇; R₃ is methyl; R₄ is

R₇ is (C₁-C₄) alkyl or benzyl; and R₁₁ is methyl substituted with one ormore fluorine atoms.

In still other embodiments, R₁ is hydrogen (C₁-C₄) alkyl or (C₁-C₄)alkyl substituted with one or more fluorine atoms; R₂ is alkyl, acyl,halo, —NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅,—CO₂R₁₀₆ or —O₂CR₁₀₇; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, (C₁-C₄) alkyl or benzyl; R₇ is(C₁-C₄) alkyl or benzyl; R₈ is hydrogen, OH, or (C₁-C₄) alkyl; R₉ ishydrogen, OH, (C₁-C₄) alkyl; R₁₀ is hydrogen, OH or (C₁-C₄) alkyl; andR₁₁ is methyl substituted with one or more fluorine atoms. In stillother embodiments, R₁ is hydrogen (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, acyl, halo,—NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or—O₂CR₁₀₇; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, R₇ is (C₁-C₄) alkyl or (C₁-C₄)substituted alkyl; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; andR₁₁ is methyl substituted with one or more fluorine atoms. In stillother embodiments, R₁ is hydrogen (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, acyl, halo,—NO₂, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃, —CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or—O₂CR₁₀₇; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₆ is hydrogen, R₇ is benzyl or (C₁-C₄) substitutedbenzyl; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; and R₁₁ ismethyl substituted with one or more fluorine atoms.

In other embodiments, R₁ is hydrogen, methyl or methyl substituted withone or more fluorine atoms; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₇ is (C₁-C₄) alkyl or benzyl; R₁₁ is methyl substituted with one ormore fluorine atoms; and n is 0.

In still other embodiments, R₁ is hydrogen or (C₁-C₄) alkyl substitutedwith one or more fluorine atoms; R₃ is hydrogen or (C₁-C₃) alkyl; R₄ is

R₅ is (C₁-C₄) alkyl; R₇ is (C₁-C₄) alkyl or benzyl; R₁₁ is methylsubstituted with one or more fluorine atoms; and n is 0.

In still other embodiments, R₁ is hydrogen; R₃ is hydrogen or methyl; R₄is

R₇ is (C₁-C₄) alkyl or benzyl; R₁₁ is methyl substituted with one ormore fluorine atoms; and n is 0.

In some of the above embodiments, R₁₁ is —CF₃.

In some embodiments, the 2-trifluoro methyl (i.e., the hydrogen atomadjacent to the indole nitrogen of the parent compound is substitutedwith trifluoromethyl) analog of methysergide, dihydromethysergide,ergocristine, dihydroergocristine, α-ergocristine,α-dihydroergocristine, β-ergocristine, β-dihydroergocristine,dihydroergocorine and dihydroergocorine are provided.

In some embodiments, a compound having the structure:

is provided.

In other embodiments, a compound having the structure:

is provided.

In still other embodiments, a compound having the structure:

is provided.

In still other embodiments, a compound having the structure:

is provided.

In some embodiments, a compound having the structure:

where R₇ is (C₁-C₄) alkyl is provided.

In other embodiments, a compound having the structure:

where R₇ is (C₁-C₄) alkyl is provided.

In still other embodiments, a compound having the structure:

where R₇ is (C₁-C₄) alkyl is provided.

In still other embodiments, a compound having the structure:

where R₇ is (C₁-C₄) alkyl is provided.

Exemplary methods for the preparation of compounds of Formula (I) and(H) for use in the compositions and methods provided herein aredescribed below and in the Examples but other methods known in the artcan be used to prepare the fluoroergoline derivatives disclosed herein.

In some embodiments, direct functionalization of 2-unsubstituted analogsof compounds of Formula (I) and (II) (e.g., compounds of Formula (III)and (IV)), for example, with an alkyl halide under basic conditions canbe used to provide the compounds of Formula (I) and (II).

In other embodiments, carboxylic acids (V) and (VI) which can beprepared by methods well known to those of skill in the art can be usedprovide compounds of Formulas (I) and (II) by acylation reactions.

Many methods exist for conversion of carboxylic (IV) and (V) tocompounds of Formulas (I) and (II), respectively. Accordingly,preparation of amides (I) and (II) from carboxylic acids (I) and (II)are well within the ambit of the skilled artisan.

Compositions and Methods of Administration

The compositions provided herein contain therapeutically effectiveamounts of one or more of the compounds provided herein that are usefulin the prevention, treatment, or amelioration of one or more of thesymptoms of diseases or disorders described herein and a vehicle.Vehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the sole activeingredient in the composition or may be combined with other activeingredients.

The compositions contain one or more compounds provided herein. Thecompounds are, in some embodiments, formulated into suitablepreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as topical administration,transdermal administration and oral inhalation via nebulizers,pressurized metered dose inhalers and dry powder inhalers. In someembodiments, the compounds described above are formulated intocompositions using techniques and procedures well known in the art (see,e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition(1999).

In the compositions, effective concentrations of one or more compoundsor derivatives thereof is (are) mixed with a suitable vehicle. Thecompounds may be derivatized as the corresponding salts, esters, enolethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals,acids, bases, solvates, ion-pairs, hydrates or prodrugs prior toformulation, as described above. The concentrations of the compounds inthe compositions are effective for delivery of an amount, uponadministration that treats, leads to prevention, or amelioration of oneor more of the symptoms of diseases or disorders described herein. Insome embodiments, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction of acompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved, prevented, or one or more symptoms areameliorated.

The active compound is included in the vehicle in an amount sufficientto exert a therapeutically useful effect in the absence of undesirableside effects on the patient treated. The therapeutically effectiveconcentration may be predicted empirically by testing the compounds inin vitro and in vivo systems well known to those of skill in the art andthen extrapolated therefrom for dosages for humans. Human doses are thentypically fine-tuned in clinical trials and titrated to response.

The concentration of active compound in the composition will depend onabsorption, inactivation and excretion rates of the active compound, thephysicochemical characteristics of the compound, the dosage schedule,and amount administered as well as other factors known to those of skillin the art. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of diseases or disorders asdescribed herein.

In some embodiments, a therapeutically effective dosage should produce aserum concentration of active ingredient of from about 0.001 ng/ml toabout 50-200 μg/ml. The compositions, in other embodiments, shouldprovide a dosage of from about 0.0001 mg to about 70 mg of compound perkilogram of body weight per day. Dosage unit forms are prepared toprovide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or5000 mg, and in some embodiments from about 10 mg to about 500 mg of theactive ingredient or a combination of essential ingredients per dosageunit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used such as use of liposomes,prodrugs, complexation/chelation, nanoparticles, or emulsions ortertiary templating. Such methods are known to those of skill in thisart, and include, but are not limited to, using co-solvents, such asdimethylsulfoxide (DMSO), using surfactants or surface modifiers, suchas TWEEN®, complexing agents such as cyclodextrin or dissolution byenhanced ionization (i.e. dissolving in aqueous sodium bicarbonate).Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedvehicle. The effective concentration is sufficient for ameliorating thesymptoms of the disease, disorder or condition treated and may beempirically determined.

The compositions are provided for administration to humans and animalsin indication appropriate dosage forms, such as dry powder inhalers(DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets,capsules, pills, sublingual tapes/bioerodible strips, tablets orcapsules, powders, granules, lozenges, lotions, salves, suppositories,fast melts, transdermal patches or other transdermal applicationdevices/preparations, sterile parenteral solutions or suspensions, andoral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or derivatives thereof. Thetherapeutically active compounds and derivatives thereof are, in someembodiments, formulated and administered in unit-dosage forms ormultiple-dosage forms. Unit-dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired vehicle. Examples of unit-dose forms include ampoules andsyringes and individually packaged tablets or capsules. Unit-dose faunsmay be administered in fractions or multiples thereof. A multiple-doseform is a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

Liquid compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional adjuvants in a vehicle, such as, for example, water, saline,aqueous dextrose, glycerol, glycols, ethanol, and the like, to therebyform a solution or suspension, colloidal dispersion, emulsion orliposomal formulation. If desired, the composition to be administeredmay also contain minor amounts of nontoxic auxiliary substances such aswetting agents, emulsifying agents, solubilizing agents, pH bufferingagents and the like, for example, acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, and other such agents.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975 or later editions thereof.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from vehicle or carrier maybe prepared. Methods for preparation of these compositions are known tothose skilled in the art. The contemplated compositions may contain0.001%400% active ingredient, in one embodiment 0.1-95%, in anotherembodiment 0.4-10%.

In certain embodiments, the compositions are lactose-free compositionscontaining excipients that are well known in the art and are listed, forexample, in the US. Pharmacopeia (USP) 25-NF20 (2002). In general,lactose-free compositions contain active ingredients, a binder/filler,and a lubricant in compatible amounts. Particular lactose-free dosageforms contain active ingredients, microcrystalline cellulose,pre-gelatinized starch, and magnesium stearate.

Further provided are anhydrous compositions and dosage forms comprisingactive ingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted as a means of simulating long-term storage in order todetermine characteristics such as shelf-life or the stability offormulations over time. See, e.g., Jens T. Carstensen, Drug Stability:Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate the decomposition of somecompounds. Thus, the effect of water on a formulation can be of greatsignificance since moisture and/or humidity are commonly encounteredduring manufacture, handling, packaging, storage, shipment, and use offormulations.

Anhydrous compositions and dosage forms provided herein can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions.

An anhydrous composition should be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions aregenerally packaged using materials known to prevent exposure to watersuch that they can be included in suitable formulary kits. Examples ofsuitable packaging include, but are not limited to, hermetically sealedfoils, plastics, unit dose containers (e.g., vials), blister packs, andstrip packs.

Oral dosage forms are either solid, gel or liquid. The solid dosageforms are tablets, capsules, granules, and bulk powders. Types of oraltablets include compressed, chewable lozenges and tablets which may beenteric-coated, sugar-coated or film-coated. Capsules may be hard orsoft gelatin capsules, while granules and powders may be provided innon-effervescent or effervescent form with the combination of otheringredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms such asfor example, capsules or tablets. The tablets, pills, capsules, trochesand the like can contain one or more of the following ingredients, orcompounds of a similar nature: a binder; a lubricant; a diluent; aglidant; a disintegrating agent; a coloring agent; a sweetening agent; aflavoring agent; a wetting agent; an enteric coating; a film coatingagent and modified release agent. Examples of binders includemicrocrystalline cellulose, methyl paraben, polyalkyleneoxides, gumtragacanth, glucose solution, acacia mucilage, gelatin solution,molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose andstarch and starch derivatives. Lubricants include talc, starch,magnesium/calcium stearate, lycopodium and stearic acid. Diluentsinclude, for example, lactose, sucrose, trehalose, lysine, leucine,lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate and advanced coloring or anti-forgery color/opalescentadditives known to those skilled in the art. Sweetening agents includesucrose, lactose, mannitol and artificial sweetening agents such assaccharin, and any number of spray dried flavors. Flavoring agentsinclude natural flavors extracted from plants such as fruits andsynthetic blends of compounds which produce a pleasant sensation or maskunpleasant taste, such as, but not limited to peppermint and methylsalicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Enteric-coatings include fatty acids, fats, waxes,shellac, ammoniated shellac and cellulose acetate phthalates. Filmcoatings include hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate. Modifiedrelease agents include polymers such as the Eudragit© series andcellulose esters.

The compound, or derivative thereof, can be provided in a compositionthat protects it from the acidic environment of the stomach. Forexample, the composition can be formulated in an enteric coating thatmaintains its integrity in the stomach and releases the active compoundin the intestine. The composition may also be formulated in combinationwith an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H₂ blockers, and diuretics. The activeingredient is a compound or derivative thereof as described herein.Higher concentrations, up to about 98% by weight of the activeingredient may be included.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles usedin elixirs include solvents. Syrups are concentrated aqueous solutionsof a sugar, for example, sucrose, and may contain a preservative. Anemulsion is a two-phase system in which one liquid is dispersed in theform of small globules throughout another liquid. Carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use suspending agents and preservatives. Acceptablesubstances used in non-effervescent granules, to be reconstituted into aliquid oral dosage form, include diluents, sweeteners and wettingagents. Acceptable substances used in effervescent granules, to bereconstituted into a liquid oral dosage form, include organic acids anda source of carbon dioxide. Coloring and flavoring agents are used inall of the above dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Sweetening agents include sucrose, syrups, glycerin andartificial sweetening agents such as saccharin. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene lauryl ether. Organic acids includecitric and tartaric acid. Sources of carbon dioxide include sodiumbicarbonate and sodium carbonate. Coloring agents include any of theapproved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from plants suchfruits, and synthetic blends of compounds which produce a pleasant tastesensation.

For a solid dosage form, the solution or suspension, in for example,propylene carbonate, vegetable oils or triglycerides, is in someembodiments encapsulated in a gelatin capsule. Such solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, thesolution, e.g., for example, in a polyethylene glycol, may be dilutedwith a sufficient quantity of a liquid vehicle, e.g., water, to beeasily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. RE28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpolyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane,diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether,polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethylether wherein 350, 550 and 750 refer to the approximate averagemolecular weight of the polyethylene glycol, and one or moreantioxidants, such as butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a acetal. Alcohols used in these formulations areany water-miscible solvents having one or more hydroxyl groups,including, but not limited to, propylene glycol and ethanol. Acetalsinclude, but are not limited to, di(lower alkyl) acetals of lower alkylaldehydes such as acetaldehyde diethyl acetal.

Parenteral administration, in some embodiments characterized byinjection, either subcutaneously, intramuscularly or intravenously isalso contemplated herein. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. The injectables, solutions and emulsions also contain one ormore excipients. Suitable excipients are, for example, water, saline,dextrose, glycerol or ethanol. In addition, if desired, the compositionsto be administered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained (see, e.g., U.S. Pat. No.3,710,795) is also contemplated herein. Briefly, a compound providedherein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Vehicles used in parenteral preparations include aqueous vehicles,nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers,antioxidants, local anesthetics, suspending and dispersing agents,emulsifying agents, sequestering or chelating agents and othersubstances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween® 80). A sequestering or chelatingagent of metal ions includes EDTA. Carriers also include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles;and sodium hydroxide, hydrochloric acid, citric acid or lactic acid forpH adjustment.

The concentration of compound is adjusted so that an injection providesan effective amount to produce the desired pharmacological effect. Theexact dose depends on the age, weight, body surface area and conditionof the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In someembodiments, a therapeutically effective dosage is formulated to containa concentration of at least about 0.01% w/w up to about 90% w/w or more,in certain embodiments more than 0.1% w/w of the active compound to thetreated tissue(s).

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108;5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634.Such dosage forms can be used to provide slow or controlled-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,can be readily selected for use with the active ingredients providedherein.

All controlled-release products have a common goal of improving drugtherapy over that achieved by their non-controlled counterparts.Ideally, the use of an optimally designed controlled-release preparationin medical treatment is characterized by a minimum of drug substancebeing employed to cure or control the condition in a minimum amount oftime. Advantages of controlled-release formulations include extendedactivity of the drug, reduced dosage frequency, and increased patientcompliance. In addition, controlled-release formulations can be used toaffect the time of onset of action or other characteristics, such asblood levels of the drug, and can thus affect the occurrence of side(e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In some embodiments, a pump may beused (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwaldet al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In other embodiments, polymeric materials can be used. In otherembodiments, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, vol. 2, pp. 115-138 (1984)). In some embodiments, a controlledrelease device is introduced into a subject in proximity of the site ofinappropriate immune activation or a tumor. Other controlled releasesystems are discussed in the review by Langer (Science 249:1527-1533(1990)). The active ingredient can be dispersed in a solid inner matrix,e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active ingredientcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a derivative thereof, in a suitable solvent. Thesolvent may contain an excipient which improves the stability or otherpharmacological component of the powder or reconstituted solution,prepared from the powder. Excipients that may be used include, but arenot limited to, an antioxidant, a buffer and a bulking agent. In someembodiments, the excipient is selected from dextrose, sorbital,fructose, corn syrup, xylitol, glycerin, glucose, sucrose and othersuitable agent. The solvent may contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to those ofskill in the art at, at about neutral pH. Subsequent sterile filtrationof the solution followed by lyophilization under standard conditionsknown to those of skill in the art provides the desired formulation. Insome embodiments, the resulting solution will be apportioned into vialsfor lyophilization. Each vial will contain a single dosage or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, the lyophilized powder is added to sterile water orother suitable carrier. The precise amount depends upon the selectedcompound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or derivatives thereof may be formulated as aerosols fortopical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols fordelivery of a steroid useful for treatment of inflammatory diseases,particularly asthma). These formulations for administration to therespiratory tract can be in the form of an aerosol or solution for anebulizer, or as a microfine powder for insufflation, alone or incombination with an inert carrier such as lactose. In such a case, theparticles of the formulation will, in some embodiments, have mass mediangeometric diameters of less than 5 microns, in other embodiments lessthan 10 microns.

Oral inhalation formulations of the compounds or derivatives suitablefor inhalation include metered dose inhalers, dry powder inhalers andliquid preparations for administration from a nebulizer or metered doseliquid dispensing system. For both metered dose inhalers and dry powderinhalers, a crystalline form of the compounds or derivatives is thepreferred physical form of the drug to confer longer product stability.

In addition to particle size reduction methods known to those skilled inthe art, crystalline particles of the compounds or derivatives can begenerated using supercritical fluid processing which offers significantadvantages in the production of such particles for inhalation deliveryby producing respirable particles of the desired size in a single step,(e.g., International Publication No. WO2005/025506). A controlledparticle size for the microcrystals can be selected to ensure that asignificant fraction of the compounds or derivatives is deposited in thelung. In some embodiments, these particles have a mass medianaerodynamic diameter of about 0.1 to about 10 microns, in otherembodiments, about 1 to about 5 microns and still other embodiments,about 1.2 to about 3. microns.

Inert and non-flammable HFA propellants are selected from HFA 134a(1,1,1,2-tetrafluoroethane) and HFA 227e(1,1,1,2,3,3,3-heptafluoropropane) and provided either alone or as aratio to match the density of crystal particles of the compounds orderivatives. A ratio is also selected to ensure that the productsuspension avoids detrimental sedimentation or cream (which canprecipitate irreversible agglomeration) and instead promote a looselyflocculated system, which is easily dispersed when shaken. Looselyfluctuated systems are well regarded to provide optimal stability forpMDI canisters. As a result of the formulation's properties, theformulation contained no ethanol and no surfactants/stabilizing agents.

The formulation of the compounds or derivatives can be administered topatients using TEMPO™, a novel breath activated metered dose inhaler.TEMPO™ overcomes the variability associated with standard pressurizedmetered dose inhalers (pMDI), and achieves consistent delivery of drugto the lung periphery where it can be systemically absorbed. To do so,TEMPO™ incorporates four novel features: 1) breath synchronoustrigger—can be adjusted for different drugs and target populations todeliver the drug at a specific part of the inspiratory cycle, 2) plumecontrol—an impinging jet to slow down the aerosol plume within theactuator, 3) vortexing chamber—consisting of porous wall, which providesan air cushion to keep the slowed aerosol plume suspended and air inletson the back wall which drive the slowed aerosol plume into a vortexpattern, maintaining the aerosol in suspension and allowing the particlesize to reduce as the HFA propellant evaporates, and 4) dosecounter—will determine the doses remaining and prevent more than theintended maximum dose to be administered from any one canister.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherexcipients can also be administered.

For nasal administration, the preparation may contain an esterifiedphosphonate compound dissolved or suspended in a liquid carrier, inparticular, an aqueous carrier, for aerosol application. The carrier maycontain solubilizing or suspending agents such as propylene glycol,surfactants, absorption enhancers such as lecithin or cyclodextrin, orpreservatives.

Solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7.4, withappropriate salts.

Other routes of administration, such as transdermal patches, includingiontophoretic and electrophoretic devices, and rectal administration,are also contemplated herein.

Transdermal patches, including iotophoretic and electrophoretic devices,are well known to those of skill in the art. For example, such patchesare disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533,6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and5,860,957.

For example, dosage forms for rectal administration are rectalsuppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients. Substancesutilized in rectal suppositories are bases or vehicles and agents toraise the melting point. Examples of bases include cocoa butter(theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) andappropriate mixtures of mono-, di- and triglycerides of fatty acids.Combinations of the various bases may be used. Agents to raise themelting point of suppositories include spermaceti and wax. Rectalsuppositories may be prepared either by the compressed method or bymolding. The weight of a rectal suppository, in one embodiment, is about2 to 3 gm. Tablets and capsules for rectal administration aremanufactured using the same substance and by the same methods as forformulations for oral administration.

The compounds provided herein, or derivatives thereof, may also beformulated to be targeted to a particular tissue, receptor, or otherarea of the body of the subject to be treated. Many such targetingmethods are well known to those of skill in the art. All such targetingmethods are contemplated herein for use in the instant compositions. Fornon-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570,6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534,5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

In some embodiments, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable ascarriers. These may be prepared according to methods known to thoseskilled in the art. For example, liposome formulations may be preparedas described in U.S. Pat. No. 4,522,811. Briefly, liposomes such asmultilamellar vesicles (MLV's) may be formed by drying down phosphatidylcholine and phosphatidyl serine (7:3 molar ratio) on the inside of aflask. A solution of a compound provided herein in phosphate bufferedsaline lacking divalent cations (PBS) is added and the flask shakenuntil the lipid film is dispersed. The resulting vesicles are washed toremove unencapsulated compound, pelleted by centrifugation, and thenresuspended in PBS.

The compounds or derivatives may be packaged as articles of manufacturecontaining packaging material, a compound or derivative thereof providedherein, which is effective for treatment, prevention or amelioration ofone or more symptoms of the diseases or disorders, supra, within thepackaging material, and a label that indicates that the compound orcomposition or derivative thereof, is used for the treatment, preventionor amelioration of one or more symptoms of the diseases or disorders,supra.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging products are well known tothose of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907,5,052,558 and 5,033,252. Examples of packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, bottles, and any packaging materialsuitable for a selected formulation and intended mode of administrationand treatment. A wide array of formulations of the compounds andcompositions provided herein are contemplated as are a variety oftreatments for any disease or disorder described herein.

Dosages

In human therapeutics, the physician will determine the dosage regimenthat is most appropriate according to a preventive or curative treatmentand according to the age, weight, stage of the disease and other factorsspecific to the subject to be treated. The compositions, in otherembodiments, should provide a dosage of from about 0.0001 mg to about 70mg of compound per kilogram of body weight per day. Dosage unit formsare prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500mg, 1000 mg or 5000 mg, and in some embodiments from about 10 mg toabout 500 mg of the active ingredient or a combination of essentialingredients per dosage unit form. The amount of active ingredient in theformulations provided herein, which will be effective in the preventionor treatment of a disorder or one or more symptoms thereof, will varywith the nature and severity of the disease or condition, and the routeby which the active ingredient is administered. The frequency and dosagewill also vary according to factors specific for each subject dependingon the specific therapy (e.g., therapeutic or prophylactic agents)administered, the severity of the disorder, disease, or condition, theroute of administration, as well as age, body, weight, response, and thepast medical history of the subject.

Exemplary doses of a formulation include milligram or microgram amountsof the active compound per kilogram of subject (e.g., from about 1micrograms per kilogram to about 50 milligrams per kilogram, from about10 micrograms per kilogram to about 30 milligrams per kilogram, fromabout 100 micrograms per kilogram to about 10 milligrams per kilogram,or from about 100 microgram per kilogram to about 5 milligrams perkilogram).

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compositionprovided herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. For example, the dosage administered tothe subject may be increased to improve the prophylactic or therapeuticeffect of the composition or it may be decreased to reduce one or moreside effects that a particular subject is experiencing.

In certain embodiments, administration of the same formulation providedherein may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months.

Methods of Use of the Compounds and Compositions

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases including, for example, migraine, ALS, Parkinson's disease,extra-pyramidal disorders, depression, nausea, restless legs syndrome,insomnia, aggression, Huntington's disease, dystonia, parsomnia andhyperlactinemia are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or compositions,described herein, supra, are administered.

Also provided are methods for antagonizing receptors including 5-HT_(2B)receptors and adrenergic alpha_(1A), alpha_(1D), alpha_(2c), alpha_(2A)and alpha_(2B) receptors using the compounds and compositions, describedherein. In practicing the methods, therapeutically effective amounts ofthe compounds or compositions, described herein, supra, areadministered.

Also provided are methods for agonizing the 5-HT_(1D) and 5-HT_(1B)receptors using the compounds and compositions described herein. In someembodiments, methods of selectively agonizing the 5-HT_(1D) receptorover the 5-HT_(1B) receptor using the compounds and compositionsdescribed herein are provided. In other embodiments, the compounds andcompositions described herein selectively agonizes the 5-HT_(1D)receptor over the 5-HT_(1B) receptor in a ratio of about 4:1. In stillother embodiments, the compounds and compositions described hereinselectively agonizes the 5-HT_(1D) receptor over the 5-HT_(1B) receptorin a ratio of about 30:1.

In still other embodiments, methods of reducing agonism of dopaminereceptors when compared to agonism of dopamine receptors by otherergolines, such as, for example, dihydroergotamine using the compoundsand compositions described herein is provided herein. In someembodiments, the dopamine receptor is the D₂ receptor. In practicing themethods, therapeutically effective amounts of the compounds orcompositions are administered.

Combination Therapy

The compounds and compositions disclosed herein may also be used incombination with one or more other active ingredients. In certainembodiments, the compounds may be administered in combination, orsequentially, with another therapeutic agent. Such other therapeuticagents include those known for treatment, prevention, or amelioration ofone or more symptoms associated with migraine.

It should be understood that any suitable combination of the compoundsand compositions provided herein with one or more of the abovetherapeutic agents and optionally one or more further pharmacologicallyactive substances are considered to be within the scope of the presentdisclosure. In some embodiments, the compounds and compositions providedherein are administered prior to or subsequent to the one or moreadditional active ingredients.

It should also be understood that any suitable combination of thecompounds and compositions provided herein may be used with other agentsto agonize and or antagonize the receptors mentioned above.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLES Example 1 Preparation of 2-CF₃-dihydroergotamine

To a solution of sodium metal (164.5 mg, 6.85 mmol) in liquid ammonia(50 mL) under N₂ at −78° C. was added absolute ethanol (1.40 mL, 24mmol) dropwise within 15 min and then the reaction mixture was warmed to−33° C. Stirring at this temperature for 40 min decolorized theinitially dark blue solution. The solution was cooled to −78° C. anddihydroergotamine (400 mg, 0.69 mmol) was subsequently added into theflask in portions. The reaction mixture was stirred at −78° C. until itbecame a clear solution, and then trifluormethyl iodide (1.34 g, 6.85mmol) was introduced as condensed from a cylinder within 5 min. Thetemperature of the reaction was allowed to reach −33° C. and was kept atthis temperature for 14 h while stirring. The solution was cooled to−78° C. again and ammonium carbonate (1.54 g, 16 mmol) was added. Afterstirring for 1 h at −78° C., the system was placed under vacuum, thesuspension was carefully heated (the temperature was maintained below−30° C.) and the ammonia was slowly evaporated. The remaining solidresidue was triturated with methylene chloride (80 mL) containing 1%methanol. The organic phase was filtered off, and evaporated in vacuo.The residue was purified twice by column chromatography (silica gel, 6g, 95:5 methylene chloride/MeOH) to afford 2-CF₃-dihydroergotamine (40mg, 77% purity as assessed by ¹H NMR analysis) as an amorphous yellowsolid. This product was combined with two more batches and purifiedtogether by HPLC to give 2-CF₃-dihydroergotamine (14 mg, 1%). HPLC 97.1%(AUC); ESI MS m/z 652 [C₃₄H₃₆F₃N₅O₅+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm8.18 (s, 1H), 7.42 (d, J=7.0 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.20-7.28(m, 3H), 7.14-7.20 (m, 1H), 7.01 (d, J=7.0 Hz, 1H), 6.49 (d, JT 1.8 Hz,1H), 6.25 (s, 1H), 4.72 (t, J=6.0 Hz, 1H), 3.60-3.71 (m, 1H), 3.45-3.59(m, 4H), 3.24 (dd, J=14.1, 6.3 Hz, 1H), 3.09-3.16 (m, 1H), 2.87-2.97 (m,1H), 2.64-2.81 (m, 3H), 2.50 (s, 3H), 2.43 (t, J=11.4 Hz, 1H), 2.22-2.31(m, 1H), 1.98-2.20 (m, 3H), 1.75-1.88 (m, 1H), 1.64-1.74 (m, 1H), 1.58(s, 3H).

Example 2 Agonist Activity at the 5-HT_(2B) Receptor with2-CF₃-dihydroergotamine

An Aequorin assay was conducted to monitor agonist activity for2-CF₃-dihydroergotamine against the human 5-HT_(2B) receptor. Theagonist assay was completed with 2-CF₃-dihydroergotamine atconcentrations between 0.01 nM and 20,000 nM. Percentage activationvalues were determined for 2-CF₃ dihydroergotamine at the 5-HT_(2B)receptor. Agonist selectivity was determined upon mixing CHO-K1 cellscoexpressing mitochondrial apoaequorin and recombinant human 5-HT_(2B)receptor with 2-CF₃-dihydroergotamine. The resulting emission of lightwas recorded using a luminometer. Agonist percentage activationdeterminations were obtained by comparing with the E_(max) of thereference agonist α-methyl-5-HT. The assay was performed by EuroScreenS.A., Belgium.

The data is summarized in FIG. 1 which illustrates potent agonism of the5-HT_(2B) receptor for the α-methyl-5-HT (known potent agonist of EC₅₀of 1.01 nM). Unexpectedly, 2-CF₃-dihydroergotamine shows no agonistactivity.

Example 3 Competitive Antagonist Activity of the 5-HT_(2B) Receptor with2-CF₃-dihydroergotamine

An Aequorin assay was conducted to monitor antagonist activity for2-CF₃-dihydroergotamine against the human 5-HT_(2B) receptor. Theantagonist assay was completed with 2-CF₃-dihydroergotamine at finalconcentrations between 0.005 nM and 10,000 nM. Percentage inhibitionvalues were determined for 2-CF₃ dihydroergotamine on the 5-HT_(2B)receptor. CHO-K1 cells coexpressing mitochondrial apoaequorin andrecombinant human 5-HT_(2B) receptor was mixed with2-CF₃-dihydroergotamine. A reference agonist at its EC₈₀ was theninjected into the mixture of cells and 2-CF₃-dihydroergotamine. Theresulting emission of light was recorded using a luminometer. The assaywas performed by EuroScreen S.A., Belgium.

The data is summarized in FIG. 2 which illustrates potent antagonism ofthe 5-HT_(2B) receptor for the SB204741 (known 5-HT_(2B) antagonist ofIC₅₀ of 28.83 nM), confirming assay validity. Furthermore,2-CF₃-dihydroergotamine behaves as an antagonist with IC₅₀ of 204.5 nM.

Example 4 Agonist Activity at the 5-HT_(1B) and 5-HT_(1D) Receptors with2-CF₃-dihydroergotamine

GTPγS assays were conducted to monitor agonist activities for2-CF₃-dihydroergotamine against the human 5-HT_(1B) and 5-HT_(1D)receptors, at final concentrations between 0.005 nM and 10,000 nM.2-CF₃-dihydroergotamine was mixed with a mixture of recombinant5-HT_(1B) and 5-HT_(1D) membrane extracts and GDP, and a mixture ofGTPγS and PVT-WGA beads. The mixture was shaken for 2 minutes prior to a60 min incubation. It was then centrifuged for 10 minutes and countedfor 1 minute with a Perkin Elmer TopCount reader. The resulting emissionof light was recorded using a luminometer. Agonist percentage activationdeterminations were obtained by comparing with the E_(max) of thereference agonist α-methyl-5-HT. The assay was performed by EuroScreenS.A., Belgium.

The data are summarized in FIG. 3. 2-CF₃-dihydroergotamine behaved as anagonist with both 5-HT_(1B) (EC₅₀ of 406 nM) and 5-HT_(1D) (EC₅₀ of 13.6nM). Unexpectedly, 2-CF₃-dihydroergotamine displayed high selectivity of5-HT_(1B):5-HT_(1B) (30:1).

Example 5 Agonist Activity at the D₂ Receptor with2-CF₃-dihydroergotamine

The assay was performed analogously to the assay described in Example 4.Both dihydroergotamine (EC₅₀ of 8.35 nM) and 2-CF₃-dihydroergotamine(EC₅₀ of 218 nM) have agonist activity at the D2 receptor. Unexpectedly,substitution with 2-CF3 caused significant increase in EC₅₀.

Example 6 Competitive Antagonist Activity of the Adrenergic Receptorsα_(1A) and α_(1D) Receptors with 2-CF₃-dihydroergotamine

The assays were performed analogously to the assay described in Example3. 2-CF3-dihydroergotamine is a significant antagonist of α_(1A) (IC₅₀of 207 nM) and α_(1D) (IC₅₀ of 40.19 nM) receptors.

Example 7 Competitive Antagonist Activity of the Adrenergic Receptorsα_(2A), α_(2B) and α_(2C) Receptors with 2-CF₃-dihydroergotamine

GTPγS assays were conducted to monitor antagonist activity for2-CF₃-dihydroergotamine against the human α_(2A), α_(2B) and α_(2C)receptors. 2-CF₃-dihydroergotamine behaves as a antagonist of α_(2A)(IC50 of 404 nM), α_(2B) (IC50 of 2140 nM) and α_(2C) (IC50 of 2784 nM).

Example 8 MDI Formulation

79.4 mg trifluoromethylated dihydroergotamine mesylate is dispersed in 5mL formulation, consisting of a mixture of HFA 134a(1,1,1,2-tetrafluoroethane) and HFA 227ea(1,1,1,2,3,3,3-heptafluoropropane ranging from 0-100% HFA 227ea. Productis filled using Pamasol filling equipment into aluminum aerosolcanisters through a pharmaceutically acceptable 63 μL metering valve.

Example 9 MDI Formulation with PEG

127 mg trifluoromethylated dihydroergotamine mesylate is dispersed in 8mL formulation, consisting of a mixture of 25% HFA 134a(1,1,1,2-tetrafluoroethane) and 75% HFA 227ea(1,1,1,2,3,3,3-heptafluoropropane and containing 0.1% w/v PEG 1000 as asuspension stabilizing agent. When tested for aerosol particle sizedistribution using a next generation Impactor (NGI) at 60 Lmin⁻¹, fineparticles fraction (% of emitted dose<5 μm vs. emitted dose) isanticipated to be >15%.

Example 10 MDI Formulation with Soy Lethicin

119 mg trifluoromethylated dihydroergotamine mesylate is dispersed in 5mL formulation, consisting of a mixture of 33% HFA 134a(1,1,1,2-tetrafluoroethane) and 67% HFA 227ea(1,1,1,2,3,3,3-heptafluoropropane and containing 0.01% w/v hydrogenatedsoy lecithin as a suspension stabilizing agent. When tested for aerosolparticle size distribution using a next generation Impactor (NGI) at 60Lmin⁻¹, fine particles fraction (% of emitted dose<5 μm vs. emitteddose) is anticipated to be >15%.

Example 11 MDI Formulation with Oleic Acid

79.4 mg trifluoromethylated dihydroergotamine mesylate, dissolved in 5mL formulation, consisting of a mixture of 33% HFA 134a(1,1,1,2-tetrafluoroethane) and 67% HFA 227ea(1,1,1,2,3,3,3-heptafluoropropane and containing 0.2% w/v oleic acid asa suspension stabilizing agent and 5% w/v ethanol. When tested foraerosol particle size distribution using a next generation Impactor(NGI) at 60 Lmin⁻¹, fine particles fraction (% of emitted dose<5 μm vs.emitted dose) is anticipated to be >15%.

Example 12 DPI Formulation

154 g trifluoromethylated dihydroergotamine mesylate is sandwich layeredbetween a total of 847 g inhalation grade lactose (Respitose® SV003),and then is blended on a Turbula blender at 42 rpm for 45 minutes. Theformulation is then sieved through a 125 μm aperture sieve twice andfilled (13 mg fill weight) into inhalation capsules. When tested foraerosol particle size distribution using a next generation Impactor(NGI) at 60 Lmin⁻¹, fine particles fraction (% of emitted dose<5 μm vs.emitted dose) is anticipated to be >15%.

Example 13 DPI Formulation

77 g trifluoromethylated dihydroergotamine mesylate is sandwich layeredbetween a total of 423 g inhalation grade lactose (Respitose® ML001),and is then blended with high shear mixing at 2000 rpm for 45 minutes.The formulation is then sieved through a 125 μm aperture sieve twice andfilled (13 mg fill weight) into inhalation capsules. When tested foraerosol particle size distribution using a next generation Impactor(NGI) at 60 Lmin⁻¹, fine particles fraction (% of emitted dose<5 μm vs.emitted dose) is anticipated to be >15%.

Example 14 Nasal Suspension Formulation

2% w/v trifluoromethylated dihydroergotamine mesylate is suspended usinghigh shear mixing into a formulation comprising microcrystallinecellulose (Avicel RC-591, 1.5%), dextrose (5.0%), polysorbate 80(0.007%), glycerol (4.0%), propylene glycol (1.0%), Citric acidmonohydrate (0.2%), disodium hydrogen orthophosphate, anhydrous (0.31%),phenylethyl alcohol (0.275%), benzalkonium chloride (0.02%) and water(87.69%) and is filled into borosilicate glass bottles fitted with apharmaceutically acceptable 100 μL metering valve. When tested usingstandard nasal testing equipment, shot weight is with 80-120% of targetand emitted dose from the spray actuator is >80%.

Example 15 Metabolism Study of 2-CF3 Dihydroergotamine

Metabolism of dihydroergotamine (DHE) and 2-CF3 DHE was evaluated inhuman liver microsomes. DHE mesylate and 2-CF3 DHE mesylate (1 μM each)were incubated separately with human liver microsomes (0.2 mgprotein/mL) in triplicate at 37° C. in 0.2 mL (final volume) incubationbuffer (50 mM potassium phosphate buffer, pH 7.4, 3 mM MgCl2 and 1 mMEDTA, pH7.4) with or without cofactor, NADPH-generating system. TheNADPH-generating system consisted of 1 mM NADP, pH 7.4, 5 mMglucose-6-phosphate, pH 7.4 and 1 unit/mL glucose-6-phosphatedehydrogenase. DHE was added to the incubation mixtures in water.2-CF3-DHE was added to incubation mixtures in 50:50 (v:v)acetonitrile:water. A low level of acetonitrile in the incubation wasmaintained to avoid any solvent effects on enzyme activity (typically at0.5% or lower). Reactions were initiated by the addition of theNADPH-generating system and were terminated at 0, 15, 30 and 60 minutesafter initiation by the addition of 175 μL of stop reagent(acetonitrile) containing two internal standards(4′-hydroxydiclofenac-d4 and 1′-hydroxymidazolam-d4, 200 and 50 ng/mL inthe final stopped incubation, respectively). The samples were thencentrifuged and the supernatant fractions were analyzed by LC/MS/MS toquantify the formation of 8′-OH-DHE (metabolite) in the DHE samples andDHE and 8′-0H-DHE in the 2-CF3-DHE samples. The results (shown in FIG.4) showed that both compounds (DHE and 2-CF3-DHE) were extensivelymetabolized by the human liver microsomes in the presence of NADPH. Theintrinsic clearance of 2-CF3-DHE was about 85% slower than that of DHE,which is consistent with the conclusion that the 2-CF3-DHE compound ismetabolically more stable than DHE.

Example 16 Genotox Studies of 2-CF3 Dihydroergotamine

Genotoxicity studies were performed to evaluate the potential mutagenicactivity of 2-CF3-DHE. Studies were performed to examine the ability of2-CF3-DHE to revert five histidine-requiring strains of Salmonellatyphimurium in the absence and presence of a rat liver metabolizingsystem. Results showed no statistically significant increases in therevertant numbers when the data was analyzed at the 1% level usingDunnett's test. This is consistent with the conclusion that there was noevidence of any mutagenic activity observed with 2-CF3-DHE.

Example 17 Effects of 2-CF3 Dihydroergotamine on Coronary Arteries andSaphenous Vein

Human coronary arteries and saphenous veins were set up under isometricconditions on either small vessel wire myographs or organ baths,depending on vessel size, in order to examine the influence of the testarticle on the relative changes in tension. In order to assess tissueviability, the vessel segments were constricted with a high potassiumsolution (KPSS, 62.5 mM) three times. Vessels were then pre-constrictedwith sumatriptan (1 μM) and endothelium-dependent vasorelaxationinvestigated using bradykinin (10 μM). If an artery segment failed torespond to KPSS or sumatriptan, it was not used in the next stage of theprotocol. All vessels were fully relaxed at the end of the experimentusing forskolin (10 μM).

Coronary arteries and small saphenous veins, having been cut into ringsegments of approximately 2 mm length, were attached by 40 μm diameterwire running through the lumen of the vessel to stainless steel heads in5 mL myograph baths containing PSS (physiological saline solution),aerated with 95% O2 and 5% CO2 and maintained at a temperature of 37° C.Changes in tension were recorded using a Danish Myotech isometrictransducer. The vessel segments were allowed to equilibrate for at least30 minutes after set up. Segments were processed through astandardization procedure of tension application, which reduces signalvariability and allows for optimal tissue response to be obtained priorthe pharmacological intervention. Saphenous veins which were too largeto run on myograph baths were set up in an organ bath system. Vesselswere treated in the same manner as the small vessels but were attachedto an isometric transducer in an organ bath system. Vessels wereequilibrated for at least 30 minutes after set up and then set to 10 mN(approximately 1 g) of tension.

Cumulative concentration response curves (CCRCs) were completed forvehicle control, sumatriptan (100 pM to 10 μM in half-log steps), and2-CF3 dihydroergotamine (100 pM to 10 μM in half-log steps); eachcondition n=6. For the studies using coronary arteries, as shown in FIG.5, the vehicle control displayed no change in tension during the courseof the experiments. As expected, sumatripan displayed a constrictioncurve with an EC₅₀ value of 112 nM. 2-CF3-DHE (labeled CBT001/02 in FIG.5), displayed only a very slight mean increase in tension. For thestudies using saphenous veins, CCRCs were completed for each testcondition in saphenous veins from 6 donors. As shown in FIG. 6, thevehicle control displayed no change in tension during the course of theexperiments. 2-CF3-DHE (labeled CBT001/02 in FIG. 6), displayed aresponse similar to the vehicle and induced no change in tension. Asexpected, sumatriptan produced a constriction curve with an EC₅₀ valueof 187 nM. Taken together, these data is consistent with conclusionthat, along with other properties, having an anti-migraine agent that isa selective agonist for the 5-HT_(1D) receptor over the 5-HT_(1B)receptor will minimize the undesired excessive vasoconstriction that isseen with compounds such as sumatriptan.

Example 18 Scalable, High-Yield Synthesis of 2-CF3 Dihydroergotamine

2-CF3-DHE was synthesized using the following synthesis route:

DHE mesylate (80 g) and DMSO (320 mL) were charged into a 3 L 3-neck RBFequipped with an overhead stirrer, temperature probe and N₂inlet/outlet. The mixture was agitated to obtain a clear orangesolution. Et₃N (17.22 mL, 1.05 eq.) was added to the mixture was stirredat ambient temperature for 5 minutes prior to the addition of CuOAc(0.72 g, 5 mol %). Togni's reagent (44.64 g, 1.2 eq.) dissolved in DMSO(at least 6.5 volumes) was charged into the blue mixture over 1 to 3hours at around 20° C. The mixture was kept at 20° C. for at least 30minutes. The mixture was then cooled to around 5° C. in an ice/waterbath. EtOAc (800 mL, 10 vols) was added to the dark brown mixture.Saturated NaHCO3 solution (800 mL, 10 vols) was added into the mixturein 30 minutes in a rate to keep the temperature below 20° C. The mixturewas stirred for 30 minutes and then the phases were separated in a 2 Lseparatory funnel. The organic layer was washed with saturated 1:1NaHCO3 solution/water (800 mL, 10 vols) and 10% brine solution (800 mL,10 vols). The remaining organic solution was then subjected topreparative chromatography for purification (normal phase with aminostationary phase and heptane/ethanol (80/20) as eluent). The collectedfraction showed a purity of 99.2% with 95% yield. The fractioncontaining the product were then concentrated to dryness to afford finalAPI product.

What is claimed is:
 1. A method of treating migraine in a subjectcomprising administering to the subject in need thereof atherapeutically effective amount of a compound of Formula (I) or (II):

or, polymorphs, salts, hydrates or solvates thereof, wherein: R₁ ishydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, substitutedalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃,—CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —OC(O)R₁₀₇; R₃ is hydrogen, (C₁-C₃) alkyl,(C₁-C₃) substituted alkyl or (C₁-C₃) alkyl substituted with one or morefluorine atoms; R₄ is

R₅ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl; R₆ is hydrogen,(C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substituted benzyl;R₇ is C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substitutedbenzyl; R₈ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substitutedalkyl, —CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀; R₉ is hydrogen, OH, ═O, (C₁-C₄) alkyl,(C₁-C₄) substituted alkyl, —CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃; R₁₀ is hydrogen,OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₁₄ or—CONR₁₁₅R₁₁₆; R₁₁ is (C₁-C₃) alkyl substituted with one or more fluorineatoms; R₁₀₀-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; k is 0, 1 or2; and n is 0, 1, 2 or
 3. 2. A method of agonizing the 5-HT₁D receptorin a cell comprising contacting the cell with an effective amount of acompound of Formula (I) or (II):

or, polymorphs, salts, hydrates or solvates thereof, wherein: R₁ ishydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, substitutedalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃,—CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —OC(O)R₁₀₇; R₃ is hydrogen, (C₁-C₃) alkyl,(C₁-C₃) substituted alkyl or (C₁-C₃) alkyl substituted with one or morefluorine atoms; R₄ is

R₅ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl; R₆ is hydrogen,(C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substituted benzyl;R₇ is C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substitutedbenzyl; R₈ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substitutedalkyl, —CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀; R₉ is hydrogen, OH, ═O, (C₁-C₄) alkyl,(C₁-C₄) substituted alkyl, —CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃; R₁₀ is hydrogen,OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₁₄ or—CONR₁₁₅R₁₁₆; R₁₁ is (C₁-C₃) alkyl substituted with one or more fluorineatoms; R₁₀₀-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;k is 0, 1 or 2; and n is 0, 1, 2 or
 3. 3. A method of selectivelyagonizing the 5-HT₁D receptor over the 5-HT₁B receptor in a cellcomprising contacting the cell with an effective amount of a compound ofFormula (I) or (II):

or, polymorphs, salts, hydrates or solvates thereof, wherein: R₁ ishydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl or (C₁-C₄) alkylsubstituted with one or more fluorine atoms; R₂ is alkyl, substitutedalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, —NO₂, —N₃, —OH, —S(O)_(k)R₁₀₀, —OR₁₀₁, —NR₁₀₂R₁₀₃,—CONR₁₀₄R₁₀₅, —CO₂R₁₀₆ or —OC(O)R₁₀₇; R₃ is hydrogen, (C₁-C₃) alkyl,(C₁-C₃) substituted alkyl or (C₁-C₃) alkyl substituted with one or morefluorine atoms; R₄ is

R₅ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl; R₆ is hydrogen,(C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substituted benzyl;R₇ is C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, benzyl or substitutedbenzyl; R₈ is hydrogen, OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substitutedalkyl, —CO₂R₁₀₈ or —CONR₁₀₉R₁₁₀; R₉ is hydrogen, OH, ═O, (C₁-C₄) alkyl,(C₁-C₄) substituted alkyl, —CO₂R₁₁₁ or —CONR₁₁₂R₁₁₃; R₁₀ is hydrogen,OH, ═O, (C₁-C₄) alkyl, (C₁-C₄) substituted alkyl, —CO₂R₁₁₄ or—CONR₁₁₅R₁₁₆; R₁₁ is (C₁-C₃) alkyl substituted with one or more fluorineatoms; R₁₀₀-R₁₁₆ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;k is 0, 1 or 2; and n is 0, 1, 2 or 3.